This invention relates to the prevention and treatment of cerebral insufficiency, including enhancement of receptor functioning in synapses in brain networks responsible for higher order behaviors. These brain networks are involved in cognitive abilities related to memory impairment, such as is observed in a variety of dementias, and in imbalances in neuronal activity between different brain regions, as is suggested in disorders such as schizophrenia. In a particular aspect, the invention relates to compounds useful for treatment of such conditions, and methods of using these compounds for such treatment.
The release of glutamate at synapses at many sites in mammalian forebrain stimulates two classes of postsynaptic receptors. These classes are usually referred to as AMPA/quisqualate and N-methyl-D-aspartic acid (NMDA) receptors. AMPA/quisqualate receptors mediate a voltage independent fast excitatory post-synaptic current (the fast EPSC), whereas NMDA receptors generate a voltage-dependent, slow excitatory current. Studies carried out in slices of hippocampus or cortex indicate that the AMPA receptor mediated fast EPSC is generally the dominant component by far at most glutamatergic synapses.
AMPA receptors are not evenly distributed across the brain but rather are largely restricted to telencephalon and cerebellum. These receptors are found in high concentrations in the superficial layers of neocortex, in each of the major synaptic zones of hippocampus, and in the striatal complex, as reported by Monaghan et al. in Brain Research 324:160-164 (1984). Studies in animals and humans indicate that these structures organize complex perceptual-motor processes and provide the substrates for higher-order behaviors. Thus, AMPA receptors mediate transmission in those brain networks responsible for a host of cognitive activities.
For these reasons, drugs that enhance the functioning of AMPA receptors could have significant benefits for intellectual performance. Such drugs should also facilitate memory encoding. Experimental studies, such as those reported by Arai and Lynch, Brain Research 598:173-184 (1992), indicate that increasing the size of AMPA receptor-mediated synaptic response(s) enhances the induction of long-term potentiation (LTP). LTP is a stable increase in the strength of synaptic contacts that follows repetitive physiological activity of a type known to occur in the brain during learning.
Compounds that enhance the functioning of the AMPA form of glutamate receptors facilitate the induction of LTP and the acquisition of learned tasks, as measured by a number of paradigms. See, for example, Granger et al., Synapse 15:326-329 (1993); Staubli et al., PNAS 91:777-781 (1994); Arai et al., Brain Res. 638:343-346 (1994); Staubli et al., PNAS 91:11158-11162 (1994); Shors et al., Neurosci. Let. 186:153-156 (1995); Larson et al., J. Neurosci. 15:8023-8030 (1995); Granger et al., Synapse 22:332-337 (1996); Arai et al., JPET 278:627-638 (1996); Lynch et al., Internet. Clin. Psychopharm. 11:13-19 (1996); and Lynch and Rogers, PCT Pubn. No. WO 94/02475. There is a considerable body of evidence showing that LTP is the substrate of memory. For example, compounds that block LTP interfere with memory formation in animals, and certain drugs that disrupt learning in humans antagonize the stabilization of LTP, as reported by del Cerro and Lynch, Neuroscience 49:1-6 (1992).
A possible prototype for a compound that selectively facilitates the AMPA receptor has been described by Ito et al., J. Physiol. 424:533-543 (1990). These authors found that the nootropic drug aniracetam (N-anisoyl-2-pyrrolidinone) increases currents mediated by brain AMPA receptors expressed in Xenopus oocytes without affecting responses by gamma-aminobutyric acid (GABA), kainic acid (KA), or NMDA receptors. Infusion of aniracetam into slices of hippocampus was also shown to increase the size of fast synaptic potentials without altering resting membrane properties. It has since been confirmed that aniracetam enhances synaptic responses at several sites in hippocampus, and that it has no effect on NMDA-receptor mediated potentials. See, for example, Staubli et al., Psychobiology 18:377-381 (1990) and Xiao et al., Hippocampus 1:373-380 (1991).
Aniracetam has been found to have a rapid onset and washout, and can be applied repeatedly with no apparent lasting effects, which are desirable features for behaviorally relevant drugs. Aniracetam does present several disadvantages, however. The peripheral administration of aniracetam is not likely to influence brain receptors. The drug works only at high concentrations (approx. 1.0 mM), and about 80% of the drug is converted to anisoyl-GABA following peripheral administration in humans (Guenzi and Zanetti, J. Chromatogr. 530:397-406 (1990)). The metabolite, anisoyl-GABA, has been found to have less activity than aniracetam.
A class of AMPA receptor-enhancing compounds that does not display the low potency and inherent instability characteristics of aniracetam has been described (Lynch and Rogers, PCT Pubn. No. WO 94/02475). These compounds, termed xe2x80x9cAMPAKINESxe2x80x9d(trademark), are substituted benzamides which include, for example, 1-(1,3-benzodioxol-5-ylcarbonyl)piperidine. They are chemically more stable than aniracetam and show improved bioavailability as judged by experiments performed by Positron Emission Tomography (PET) (see, for example, Staubli et al., in PNAS 91:11158-11162 (1994).
Another class of Ampakines, benzoxazines, has been discovered recently to have very high activity in in vitro and in vivo models for assessing the probability of producing cognition enhancement, as described in PCT Pubn. No. WO 97/36907, xe2x80x9cBenzoxazines for Enhancing Synaptic Responsexe2x80x9d, by Rogers and Lynch. Some, but not all, of these compounds show activity in a rat model for the human disease, schizophrenia (Larson et al., Brain Res. 728: 353-356 (1996)).
Certain substituted benzofurazan and benzothiadiazole compounds have been found to be significantly and surprisingly more potent in the animal model of schizophrenia than these previously reported compounds, and are also effective in cognition enhancement. These compounds are disclosed herein.
The present invention includes, in one aspect, compounds as shown and described in Section II of the Detailed Description, following. The compounds are effective to increase AMPA receptor-mediated responses and are thus useful for a variety of purposes. These include facilitating the learning of behaviors dependent upon AMPA receptors, treating conditions in which AMPA receptors, or synapses utilizing these receptors, are reduced in numbers or efficiency, and enhancing excitatory synaptic activity in order to restore an imbalance between brain subregions. The invention thereby provides a method for the treatment of a mammalian subject suffering from a hypoglutamatergic condition, or from a deficiency in the number or strength of excitatory synapses, or in the number of AMPA receptors, such that memory or other cognitive functions are impaired. Such conditions may also cause a cortical/striatal imbalance, leading to schizophrenia or schizophreniform behavior.
According to the method, the subject is treated with an effective amount of a compound as shown and described in Section II of the Detailed Description, following, in a pharmaceutically acceptable carrier. As demonstrated below, the compounds are significantly more potent than previously described compounds in increasing AMPA receptor function in slices of rat hippocampus, in animal models of schizophrenia and depression, and in enhancing cognitive performance, such as performance in an 8-arm radial maze.
These and other objects and features of the invention will become more fully apparent when the following detailed description of the invention is read in conjunction with the accompanying drawings.